title: Control of cellular Bcl-xL levels by deamidation-regulated degradation.
abstract: The cellular concentration of Bcl-xL is among the most important determinants of treatment response and overall prognosis in a broad range of tumors as well as an important determinant of the cellular response to several forms of tissue injury. We and others have previously shown that human Bcl-xL undergoes deamidation at two asparaginyl residues and that DNA-damaging antineoplastic agents as well as other stimuli can increase the rate of deamidation. Deamidation results in the replacement of asparginyl residues with aspartyl or isoaspartyl residues. Thus deamidation, like phosphorylation, introduces a negative charge into proteins. Here we show that the level of human Bcl-xL is constantly modulated by deamidation because deamidation, like phosphorylation in other proteins, activates a conditional PEST sequence to target Bcl-xL for degradation. Additionally, we show that degradation of deamidated Bcl-xL is mediated at least in part by calpain. Notably, we present sequence and biochemical data that suggest that deamidation has been conserved from the simplest extant metazoans through the human form of Bcl-xL, underscoring its importance in Bcl-xL regulation. Our findings strongly suggest that deamidation-regulated Bcl-xL degradation is an important component of the cellular rheostat that determines susceptibility to DNA-damaging agents and other death stimuli.
authors.affiliation: Division of Urology and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: So Hee
authors.initials: SH
authors.lastname: Dho
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Deverman
authors.forename: Carlo
authors.initials: C
authors.lastname: Lapid
authors.forename: Scott R
authors.initials: SR
authors.lastname: Manson
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Riehm
authors.forename: Rajeev
authors.initials: R
authors.lastname: Aurora
authors.forename: Ki-Sun
authors.initials: KS
authors.lastname: Kwon
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Weintraub
mesh_terms: D000577:Amides / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002154:Calpain / Q000378:metabolism; D002460:Cell Line; D017124:Conserved Sequence; D004249:DNA Damage; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D051020:bcl-X Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000577:Amides; D051020:bcl-X Protein; D002154:Calpain